Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

Abstract

Following our recently published fluorine-18 labeling method, "Radio-fluorination on the Sep-Pak", we have successfully synthesized 6-[ F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t-butanol) of its quaternary ammonium salt precursor, 6-(N,N,N-trimethylamino)nicotinaldehyde trifluoromethanesulfonate (2), through a fluorine-18 containing anion exchange cartridge (PS-HCO ). Over 80% radiochemical conversion was observed using 10 mg of precursor within 1 minute. The [ F]fluoronicotinaldehyde ([ F]5) was then conjugated with 1-(6-(aminooxy)hexyl)-1H-pyrrole-2,5-dione to prepare the fluorine-18 labeled maleimide functionalized prosthetic group, 6-[ F]fluoronicotinaldehyde O-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexyl) oxime, 6-[ F]FPyMHO ([ F]6). The current Sep-Pak method not only improves the overall radiochemical yield (50 ± 9%, decay-corrected, n = 9) but also significantly reduces the synthesis time (from 60-90 minutes to 30 minutes) when compared with literature methods for the synthesis of similar prosthetic groups.

Minimalist approach meets green chemistry: Synthesis of18F‐ labeled (hetero)aromatics in pure ethanol

“…We reasoned that, while EtOH was obviously a suboptimal solvent for aromatic nucleophilic radiofluorination, the use of more activated substrates for radiolabeling could improve RCYs. Therefore, we turned to the preparation of 6‐[ 18 F]fluoronicotinaldehyde ([ 18 F] 2 ), a prosthetic group first described by Kügler et al Whereas the preparation of [ 18 F] 2 using trimethylamine as a leaving group had already been described, we decided to evaluate 1,4‐diazabicyclo[2.2.2]octane (DABCO) as an alternative leaving group in order to avoid handling of toxic and malodorous Me 3 N. The corresponding triflate precursor was conveniently prepared by the direct reaction between 6‐chloronicotine and DABCO followed by anion metathesis with TMSOTf. Radiofluorination of both precursors in pure EtOH proceeded smoothly to render the desired radiolabeled aldehyde in 65 and 44% RCY from the Me 3 N‐ or DABCO‐substituted precursor, respectively (Figure ).…”

“…Radiofluorination of both precursors in pure EtOH proceeded smoothly to render the desired radiolabeled aldehyde in 65 and 44% RCY from the Me 3 N‐ or DABCO‐substituted precursor, respectively (Figure ). For comparison, we produced [ 18 F] 2 using the on‐cartridge protocol described by Basuli et al This procedure is a further development of the “minimalist” approach and allowed to prepare 18 F‐labeled pyridines with electron‐withdrawing substituent(s) like [ 18 F] 2 simply by slow elution of 18 F – from a Cromafix PS‐HCO 3 anion exchange cartridge, with a solution of the corresponding N , N , N ‐trimethylammonium precursor in MeCN/ t BuOH (1/4). Using this protocol [ 18 F] 2 was prepared in RCYs of 55–70%.…”

Detecting hypoxia in vitro using 18F-pretargeted IEDDA “click” chemistry in live cells

“…Accurate mass spectra were obtained via the Imperial College Department of Chemistry Mass Spectrometry service. 26 Radioactive product identity was determined by RP-HPLC using an Agilent 1200 series instrument connected to a ow-ram detector (Lablogic, Sheffield, UK). The system was equipped with a Phenomenex Gemini 5m C18 110Å (150 Â 4.6 mm) column; the mobile phase was A: H 2 O (0.1% TFA) and B: MeCN.…”

Fluorine-18 Labeled Fluorofuranylnorprogesterone ([18F]FFNP) and Dihydrotestosterone ([18F]FDHT) Prepared by “Fluorination on Sep-Pak” Method

“…Fluorine-18 was obtained from the National Institutes of Health cyclotron facility (Bethesda, MD, USA). Chromafix 30-PS-HCO 3 anion-exchange cartridge was purchased from Macherey-Nagel (Düren, Germany) and the packing material was reduced to half (~20 mg) for better elution efficiency of [ 18 F]fluoride [3]. Phenomenex Luna C18 (2) column (10 × 250 mm, 5 µm) was purchased from Phenomenex (Torrance, CA, USA).…”

“…Recently we have developed a novel method, “fluorination on Sep-Pak”, to prepare prosthetic groups for radiofluorination of biomolecules which requires neither azeotropic drying of fluorine-18 nor addition of base [1,2,3]. Hence, it is less time consuming and more suitable for base and temperature sensitive starting materials.…”